In recent years, a method for producing a preparation comprising the step of hot melt-extruding a mixture of a drug and a polymer has been attracting attentions.
For example, a solid dispersion obtained by solidifying a poorly water-soluble drug and a polymer through hot melt extrusion, contains the drug in an amorphous state and has the drug molecularly dispersed in the polymer carrier. Such a solid dispersion has notably increased apparent solubility and improved bioavailability. Since the hot melt extrusion can be carried out in the absence of a solvent, it is applicable to a drug which is instable in water. Unnecessity for the solvent recovery in the hot melt extrusion has advantages of a safety, no environmental concerns, saving energy used for a solvent recovering step, and an improvement in a safety of the workers. Further, the hot melt extrusion enables continuous production, differing from the conventional batch production systems, and attracts attentions from the standpoint of productivity and energy consumption per hour.
One of the polymers used in the hot melt extrusion is hypromellose acetate succinate (hereinafter also referred to as “HPMCAS”) obtained by introducing four kinds of the substituents in total. The HPMCAS contains two substituents of a methoxy group (—OCH3) and a hydroxypropoxy group (—OC3H6OH) introduced into a cellulose skeleton to form ether structures, and two substituents of an acetyl group (—COCH3) and a succinyl group (—COC2H4COOH) to form ester structures.
The contents of the respective substituents in HPMCAS listed in the Japanese Pharmacopoeia 16th Edition are defined as follows (Non-Patent Document 1).
TABLE 1ContentMolar substitution (% by weight)(MS) *1Methoxy group12.0 to 28.00.73 to 2.83Hydroxypropoxy group 4.0 to 23.00.10 to 1.90Acetyl group 2.0 to 16.00.09 to 2.30Succinyl group 4.0 to 28.00.08 to 1.78*1 The molar substitution means the average number of each of substituents introduced per glucose ring unit of cellulose.
Regarding a solid dispersion containing HPMCAS, for example, a method of lowering a glass transition temperature or a softening temperature of HPMCAS or a poorly water-soluble drug by adding water to a composition comprising HPMCAS (commercially available AS-LF having a molar substitution of 0.16 to 0.35) has been proposed, where the resulting mixture is then subjected to hot melt extrusion to form a solid dispersion (Patent Document 1).
A method for forming a preparation containing posaconazole, which is a poorly water-soluble drug, and HPMCAS (commercially available AS-MF or AS-MG having a molar substitution of 0.15 to 0.34) through hot melt extrusion (Patent Document 2), and a method for forming a preparation containing a lipid inhibitor CETP (cholesterol ester transfer protein), which is a poorly water-soluble drug, and HPMCAS (commercially available AS-MF having a molar substitution of 0.15 to 0.34) through hot melt extrusion (Patent Document 3) have been also proposed.
Further, a method for spray-drying a composition containing a poorly water-soluble drug and HPMCAS having a hydroxypropoxy molar substitution of 0.25, a succinyl molar substitution of 0.02 or more, an acetyl molar substitution of 0.65 or more, a total molar substitution of 0.85 or more with respect to acetyl and succinyl groups, and a glass transition temperature of 131 to 146° C. at relative humidity (RH) of 0% to form a solid dispersion has been proposed (Patent Document 4). Moreover, a method for spray-drying a composition containing a poorly water-soluble drug and HPMCAS having a hydroxypropoxy molar substitution of 0.21 or less, a methoxyl molar substitution of 1.45 or less, and a total molar substitution of 1.25 or more with respect to acetyl and succinyl groups to form a solid dispersion has been proposed (Patent Document 5).